gastroenterol 39(10) gastroenterología y hepatología

Gastroenterol Hepatol. 2016;39(10):697---721

www.elsevier.es/gastroenterologia

Gastroenterología y Hepatología

REVIEW

IV Spanish Consensus Conference on Helicobacter

pylori infection treatment�

Javier P. Gisbert a,∗,1, Javier Molina-Infanteb,1, Javier Amador c,Fernando Bermejod, Luis Bujandae, Xavier Calvet f, Manuel Castro-Fernández g,Antonio Cuadrado-Lavính, J. Ignasi Elizalde i, Emili Gene j, Fernando Gomollón k,Ángel Lanas k, Carlos Martín de Argila l, Fermín Mearinm, Miguel Montoron,Ángeles Pérez-Aisao, Emilio Pérez-Trallerop, Adrián G. McNicholl a

a Servicio de Aparato Digestivo, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP),Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spainb Servicio de Aparato Digestivo, Hospital San Pedro de Alcántara, Cáceres, Spainc Medicina de Familia, Centro de Salud Los Ángeles, Madrid, Spaind Servicio de Aparato Digestivo, Hospital Universitario de Fuenlabrada, Fuenlabrada, Madrid, Spaine Servicio de Digestivo, Hospital Donostia/Instituto Biodonostia, Universidad del País Vasco UPV/EHU, CIBEREHD, San Sebastián,Spainf Servicio de Aparato Digestivo, Hospital Parc Taulí, Universitat Autònoma de Barcelona, CIBEREHD, Sabadell, Barcelona, Spaing Servicio de Aparato Digestivo, Hospital Universitario de Valme, CIBEREHD, Sevilla, Spainh Servicio Aparato Digestivo, Hospital Universitario Marqués de Valdecilla, Santander, Spaini Servicio de Aparato Digestivo, Hospital Clínic, CIBEREHD, Barcelona, Spainj Servicio de Urgencias, Hospital Parc Taulí Sabadell, CIBEREHD, Universitat Internacional de Catalunya, Sabadell, Barcelona,Spaink Servicio de Aparato Digestivo, Hospital Clínico Universitario de Zaragoza, IIS Aragón, CIBEREHD, Zaragoza, Spainl Servicio de Aparato Digestivo, Hospital Universitario Ramón y Cajal, Universidad de Alcalá, Madrid, Spainm Servicio de Aparato Digestivo, Centro Médico Teknon, Barcelona, Spainn Servicio de Aparato Digestivo, Hospital San Jorge, Huesca, Spaino Servicio de Aparato Digestivo, Agencia Sanitaria Costa del Sol, Marbella, Málaga, Spainp Servicio de Microbiología, Hospital Donostia/Instituto Biodonostia, Universidad del País Vasco UPV/EHU, CIBEREHD,San Sebastián, Spain

Received 25 April 2016; accepted 19 May 2016Available online 26 November 2016

� Please cite this article as: Gisbert JP, Molina-Infante J, Amador J, Bermejo F, Bujanda L, Calvet X, et al. IV Conferencia Espanola deConsenso sobre el tratamiento de la infección por Helicobacter pylori. Gastroenterol Hepatol. 2016;39:697---721.

∗ Corresponding author.E-mail address: [email protected] (J.P. Gisbert).

1 Both these authors have contributed equally to the consensus.

2444-3824/© 2016 Elsevier Espana, S.L.U., AEEH and AEG. All rights reserved.

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698 J.P. Gisbert et al.

KEYWORDSBismuth;Clarithromycin;Helicobacter pylori;Proton pumpinhibitor;Metronidazole;Omeprazole

Abstract Helicobacter pylori approximately infect 50% of Spanish population and causeschronic gastritis, peptic ulcer and gastric cancer. Until now, three consensus meetings on H.pylori infection had been performed in Spain (the last in 2012). The changes in the treatmentschemes, and the increasing available evidence, have justified organising the IV Spanish Consen-sus Conference (March 2016), focused on the treatment of this infection. Nineteen expertsparticipated, who performed a systematic review of the scientific evidence and developed aseries of recommendation that were subjected to an anonymous Delphi process of iterative vot-ing. Scientific evidence and the strength of the recommendation were classified using GRADEguidelines. As starting point, this consensus increased the minimum acceptable efficacy ofrecommended treatments that should reach, or preferably surpass, the 90% cure rate whenprescribed empirically. Therefore, only quadruple therapies (with or without bismuth), andgenerally lasting 14 days, are recommended both for first and second line treatments. Non-bismuth quadruple concomitant regimen, including a proton pump inhibitor, clarithromycin,amoxicillin and metronidazole, is recommended as first line. In the present consensus, otherfirst line alternatives and rescue treatments are also reviewed and recommended.© 2016 Elsevier Espana, S.L.U., AEEH and AEG. All rights reserved.

PALABRAS CLAVEBismuto;Claritromicina;Helicobacter pylori;Inhibidor de la bombade protones;Metronidazol;Omeprazol

IV Conferencia Espanola de Consenso sobre el tratamiento de la infecciónpor Helicobacter pylori

Resumen La infección por Helicobacter pylori afecta aproximadamente al 50% de la poblaciónespanola y es causante de la gastritis crónica, la úlcera péptica y el cáncer gástrico. Se hanllevado a cabo hasta el momento, en nuestro país, 3 reuniones de Consenso sobre el manejode la infección por H. pylori (la última de ellas en 2012). Los cambios en los esquemas detratamiento y la creciente evidencia disponible al respecto han justificado la organización deesta IV Conferencia Espanola de Consenso en marzo de 2016, centrada en el tratamiento de estainfección. Participaron 19 expertos sobre el tema, que realizaron una búsqueda sistemática dela evidencia científica y elaboraron una serie de recomendaciones que fueron sometidas a unproceso de interacción de votaciones anónimas seriadas mediante metodología Delphi. Paraclasificar la evidencia científica y la fuerza de las recomendaciones se utilizó el sistema GRADE.Este consenso establece, como punto de partida, un aumento de la exigencia en la eficacia de lostratamientos recomendados, que deben alcanzar, o preferiblemente superar, el 90% de curaciónal ser administrados de forma empírica. De este modo, tanto en primera como en segunda línease recomiendan tratamientos cuádruples con o sin bismuto, generalmente prescritos durante14 días. El tratamiento cuádruple sin bismuto concomitante, que incluye un inhibidor de labomba de protones, claritromicina, amoxicilina y metronidazol, se recomienda como primeralínea. En el presente consenso se revisan también con detalle otras alternativas de tratamientotanto de primera línea como de rescate.© 2016 Elsevier Espana, S.L.U., AEEH y AEG. Todos los derechos reservados.

Introduction

Helicobacter pylori infection affects around 50% of the worldpopulation, and plays a key role in the development ofvarious gastrointestinal diseases such as chronic gastritis,peptic ulcer and gastric cancer, so proper diagnosis andeffective treatment are essential in clinical practice. Sev-eral Consensus Conferences have hitherto been organised onthe diagnosis and treatment of infection by this microorgan-ism in the United States, Europe and Asia. Three Consensusmeetings on the diagnosis and treatment of H. pylori infec-tion have been held thus far in Spain: in 1999,1,2 in 20043,4

and in 2012.5 The notable changes made in treatment

regimens and growing evidence in support of these promptedthe organisation of a fourth Spanish Consensus Conference,held in March 2016. Since there have been no relevant break-throughs in aspects related with treatment indications ordiagnostic techniques, this Consensus Conference focusedexclusively on updating the recommendations for the treat-ment of H. pylori infection.

Methodology

Conference participants. All the experts who participatedin the last Consensus Conference held in 2012 wereinvited.3 Researchers named as first author on any article on

IV Spanish Consensus Conference on H. pylori 699

treatment of H. pylori infection published in the last 4 years(identified using the search strategy ‘‘helicobacter pyloriAND Spain’’ in PubMed) were also asked to attend. A total of19 experts were invited, with 18 (95%) eventually participat-ing, including gastroenterologists, microbiologists, primarycare physicians and experts in scientific methodology andevidence-based medicine. Two gastroenterologists (JPG andJMI) acted as coordinators.

Literature searches. Systematic reviews and other crit-ical synthesis documents in the scientific literature werefirst identified. The following electronic databases wereconsulted: TRIP Database, NHS National Library of Guide-lines, National Guideline Clearinghouse, Cochrane Databaseof Systematic Reviews (The Cochrane Library), Databaseof Abstracts of Reviews of Effects (DARE) and MEDLINE(accessed by PubMed). The second phase consisted of asearch for individual studies, randomised clinical trials andobservational studies, as well as a review of the bibliogra-phical references cited in the documents included.

Grading the quality of scientific evidence and thestrength of recommendations. The Grading of Recommen-dations Assessment, Development and Evaluation (GRADE)system (http://www.gradeworkinggroup.org/) was used tograde the quality of the scientific evidence and the strengthof the recommendations. GRADE, a clear structured clas-sification system that is being widely adopted in theinternational setting, has the advantage of overcoming thelimitations of previous systems and standardising the formu-lation of guidelines by all institutions.6,7

Evaluation of the recommendations by the consensusgroup. The recommendations were initially drawn up by thecoordinators and then submitted to an interactive, anony-mous serial voting system using the Delphi methodology.8

Three rounds of voting took place, 2 online and 1 in per-son. The online procedure was carried out using the REDCap(research electronic data capture) system, a software appli-cation hosted on the Spanish Association of Gastroenterology(AEG) server (https://redcap.aegastro.es/).9 AEG is a non-profit medical-scientific society dedicated to research andtraining in the field of gastroenterology, and offers this ser-vice free of charge with the sole aim of promoting researchled by independent investigators. REDCap is a secure web-based application designed to support data capture forresearch studies, offering: (1) an intuitive interface for com-piling validated data; (2) traceability of data manipulation,access and export; (3) automated procedures for seamlessdata downloads to common statistical programmes, and (4)procedures for importing data from external sources.

The participants rated their agreement with each recom-mendation on a 6-point Likert scale (1: completely disagree;2: mostly disagree; 3: somewhat disagree; 4: somewhatagree; 5: mostly agree; 6: completely agree). Any scoreunder 6 required the coordinators to review each section ofthat recommendation (wording, grade of evidence, strengthof the recommendation and rationale), and to make sugges-tions for improvement. After each vote, the 2 coordinatorsgathered together the comments and votes received foreach recommendation, integrating the suggestions to max-imise the agreement.

The recommendations that emerged from the 2 roundsof online voting were discussed and approved during an in-person meeting held in Madrid on 1 March 2016, chaired

by the 2 coordinators (JPG and JMI). During the meeting,the recommendations were reviewed, amended (when nec-essary) and submitted to a new vote. A recommendationwas approved if more than 75% of the participants were inagreement (score of 4---6 on the Likert scale). AGM actedas scientific secretary of the consensus, taking the minutesof the meeting, counting the votes in the various roundsof voting, recording the comments, and systematizing theincorporation of suggestions.

Ethical aspects. The consensus complied with establishedethical guidelines.10 The participants declared any conflictsof interest before and after the Delphi voting process.

Sponsorship, endorsements and funding. The conferencewas sponsored by the Spanish Biomedical Research Network-ing Centre for Liver and Digestive Diseases (CIBEREHD). ThisConsensus document has been endorsed by the Spanish Asso-ciation of Gastroenterology and by the Spanish Society ofDigestive Pathology, who have adhered to and supported theconsensus recommendations. No funding was received fromany pharmaceutical company.

Recommendations

Each recommendation is accompanied by the final vote(percentage of agreement), grade of recommendation (GR;strong or weak), certainty in the evidence (CE; high, mod-erate, low or very low) and discussion of the correspondingevidence.

All the recommendations approved in the present Span-ish Consensus on the treatment of H. pylori infection areincluded in Table 1. The drugs, duration and dose of eachcomponent included in the recommended regimens are bro-ken down in Table 2. Finally, the algorithm for initial andrescue treatment of the infection is shown in Fig. 1.

Since the advantage of guiding eradication therapy bystudying the antimicrobial susceptibility of the H. pyloristrain versus empirical administration of treatment hasnot been sufficiently confirmed,11,12 and since this test isnot generally accessible,13 the comments included in thisconsensus document will be based on the assumption thatthis susceptibility is unknown.

• Recommendation 1. It is currently recommended thatan eradication treatment be considered effective when itcan cure H. pylori infection in close to, or preferably morethan, 90% of patients.

Agreement: 92.3%; votes: completely agree (84.6%);mostly agree (7.7%); completely disagree (7.7%). GR: strong.CE: very low.

The goal of therapy aimed at eliminating any microor-ganism should be to reach a 100% success rate, and H. pyloriinfection should be no exception.14 However, all previousEuropean15---18 and Spanish2,4,5 consensus documents haveestablished that a cure rate greater than or equal to80% could be considered sufficient. Given that quadrupletherapies with cure rates close to or even higher than90% are currently available,19,20 it was considered thatthis efficacy threshold should henceforth be required toconsider treatment for H. pylori infection effective. To

http://www.gradeworkinggroup.org/

https://redcap.aegastro.es/


Table 1 Recommendations for the treatment of Helicobacter pylori infection.

Recommendation 1. It is currently recommended that an eradication treatment be considered effective when it can cureH. pylori infection in close to, or preferably more than, 90% of patients.

Recommendation 2. A non-bismuth quadruple concomitant regimen (PPI, clarithromycin, amoxicillin and metronidazole)is recommended as first-line treatment of H. pylori infection.

Recommendation 3. Bismuth-containing quadruple therapy (PPI, bismuth, tetracycline and metronidazole) could be analternative first-line eradication treatment once its efficacy has been confirmed in our setting.

Recommendation 4. The recommended duration of non-bismuth quadruple concomitant therapy (PPI, clarithromycin,amoxicillin and metronidazole) is 14 days.

Recommendation 5. The suggested duration of bismuth-containing quadruple therapy (PPI, bismuth, tetracycline andmetronidazole) is 10 or 14 days.

Recommendation 6. A bismuth-containing quadruple regimen (PPI, bismuth, tetracycline and metronidazole) isrecommended as first-line treatment in patients allergic to penicillin.

Recommendation 7. Probiotics should not be indiscriminately combined with eradication treatment.Recommendation 8. Following failure of a first treatment that includes clarithromycin (triple or quadruple), a regimen,

preferably quadruple, that includes levofloxacin is recommended, preferably quadruple (PPI, amoxicillin, levofloxacinand bismuth). Another alternative is bismuth-containing quadruple therapy (PPI, bismuth, tetracycline andmetronidazole).

Recommendation 9. Following failure of a first treatment with a bismuth-containing quadruple regimen (PPI, bismuth,tetracycline and metronidazole), a levofloxacin-containing triple or quadruple regimen is recommended (PPI,amoxicillin, levofloxacin ± bismuth).

Recommendation 10. Rescue treatment in penicillin-allergic patients:(a) After failure of a first triple treatment (PPI, clarithromycin and metronidazole), bismuth-containing quadrupletherapy (PPI, bismuth, tetracycline and metronidazole) is suggested.(b) After failure of a first bismuth-containing quadruple treatment, triple therapy with PPI, levofloxacin andclarithromycin is suggested.

Recommendation 11. Following failure of a first treatment with clarithromycin and a second line with levofloxacin, abismuth-containing quadruple treatment (PPI, bismuth, tetracycline and metronidazole) treatment is recommended.

Recommendation 12. Following failure of a first treatment with clarithromycin and a second-line bismuth-containingquadruple treatment (PPI, bismuth, tetracycline and metronidazole), a levofloxacin-containing treatment isrecommended.

Recommendation 13. Following failure of a first bismuth-containing quadruple treatment (PPI, bismuth, tetracycline andmetronidazole), and a second-line levofloxacin-containing regimen, quadruple concomitant treatment (PPI,amoxicillin, clarithromycin and metronidazole) is suggested.

Recommendation 14. Following the failure of a third treatment, it is suggested that the need to eradicate the infectionshould be re-evaluated and, if applicable, a fourth line with rifabutin (PPI, amoxicillin and rifabutin) should beprescribed.

Recommendation 15. In patients with uncomplicated duodenal ulcer who do not require NSAID/aspirin, antisecretorytreatment should not be maintained after completing H. pylori eradication treatment.

Recommendation 16. In patients with gastric ulcer who do not require NSAID/aspirin, antisecretory treatment should bemaintained for 4 to 8 weeks after completing H. pylori eradication treatment.

Recommendation 17. In patients with gastrointestinal bleeding due to peptic ulcer, eradication of H. pylori eliminatesvirtually all recurrences; therefore, once the eradication has been confirmed, and in the absence of NSAID/aspirin use,antisecretory maintenance treatment should not be administered.

achieve this goal, all treatments should be optimised interms of duration, dose and frequency of proton pumpinhibitor (PPI) and antibiotic administration.21

• Recommendation 2. A non-bismuth quadruple conco-mitant regimen (PPI, clarithromycin, amoxicillin andmetronidazole) is recommended as first-line treatment ofH. pylori infection.

Agreement: 100%; votes: completely agree: (100%). GR:strong. CE: moderate.

The choice of first-line treatment for H. pylori infectionwill depend primarily on the rate of resistance of this bac-terium to the antibiotics prescribed. Standard triple therapy(PPI, clarithromycin and amoxicillin) is not recommendedwhen the rate of resistance to clarithromycin is >15%,18

since the eradication rates are unacceptably low abovethis threshold.21 Other factors that affect the efficacy oferadication treatment are patient compliance and their pre-vious history of antibiotic use, which could determine thechoice of first treatment option.21 The evidence availablewith respect to the different first-line treatment regimensis reviewed below.


Table 2 Drugs, doses and duration of eradication treatments for Helicobacter pylori infection.

Treatment Drugs Posology Duration (days)

Non-bismuth quadruple therapy (concomitant) PPI Standard dosea/12 h 14Amoxicillin 1 g/12 hClarithromycin 500 mg/12 hMetronidazole 500 mg/12 h

Bismuth-containing quadruple therapy Pylera PPI Standard dose/12 h 10Pylera 3 capsules/6 h

Standard bismuth-containing quadruple therapy PPI Standard dose/12 h 10---14Bismuth subcitrate 120 mg/6 h or 240 mg/12 hDoxycyclineb 100 mg/12 hMetronidazole 500 mg/8 h

Quadruple therapy with levofloxacin and bismuth PPI Standard dosea/12 h 14Amoxicillin 1 g/12 hLevofloxacin 500 mg/24 hBismuth subcitrate 240 mg/12 h

Triple therapy with levofloxacin PPI Standard dose/12 h 14Amoxicillin 1 g/12 hLevofloxacin 500 mg/24 h

Triple therapy with rifabutin PPI Standard dose/12 h 10Amoxicillin 1 g/12 hRifabutin 150 mg/12 h

PPI: proton pump inhibitor.a In contrast to standard triple treatment, the benefit of administering the latest PPIs (rabeprazole or esomeprazole) and the use of

double doses of these is not clearly established; however, it is likely that these improvements also add eradication benefits to thesetherapeutic regimens.

b Although tetracycline hydrochloride is usually recommended, this antibiotic is not currently marketed in Spain, so doxycycline canbe used instead (although experience is much more limited and there are doubts about its therapeutic equivalence).

Allergic to penicillin?No

PPI/12 h

Amoxicillin 1 g/12 h

Clarithromycin 500 mg/12 h

Metronidazole 500 mg/12 h

14 days

∗ †

†

§

†

#

#

#

PPI/12 hBismuth 120 mg/6 h

or 240 mg/12 hDoxycycline 100 mg/12 hMetronidazol 500 mg/8 h

10 or 14 days

PPI/12 h

Pylera

3 capsules/6 h

10 days

PPI/12 h

Pylera

3 capsules/6 h

10 days

PPI/12 h

Pylera

3 capsules/6 h

10 days

PPI/12 hPPI/12 h

Bismuth 120 mg/6 hor 240 mg/12 h

Doxycycline 100 mg/12 hMetronidazole 500 mg/8 h

10 or 14 days

PPI/12 h



Bismuth 240 mg/12 h

14 days

PPI/12 hBismuth 120 mg/6 h or

240 mg/12 hDoxycycline 100 mg/12 hMetronidazol 500 mg/8 h

10 or 14 days

PPI/12 h


Rifabutina 150 mg/12 h

10 days

PPI/12 h


Levofloxacin 500 mg/24 h

Bismuth 240 mg/12 h

14 days

Clarithromycin 500 mg/12 h


10 days

1st line

2nd line

3rd line

4th line

Yes

Figure 1 Algorithm for initial and rescue treatment of Helicobacter pylori infection. H: hours; PPI: proton pump inhibitor.*Bismuth-containing quadruple therapy (PPI, bismuth, tetracycline and metronidazole) could be an alternative as first-line eradi-cation treatment, once its efficacy has been confirmed in our setting. †There is a new formulation with all the antibiotics includedin a single capsule. #Tetracycline hydrochloride on its own is not marketed in Spain; doxycycline can be used instead (100 mg/12 h),although experience is much more limited and there are doubts about its therapeutic equivalence. §It is suggested to carefullyre-evaluate the need to eradicate the infection.


Table 3 Spanish studies that have evaluated the efficacy (intention-to-treat) of first-line non-bismuth quadruple concomitanttherapy in the last 5 years.

Author and year of publication Patients (n) Duration (days) Dose of PPI Eradication (%) Eradication comparator

Molina-Infante, 201230 209 10 PPI standard/12 h 86 ---Molina-Infante, 201331 170 14 Omeprazole

40 mg/12 h91.7 90%

Hybrid, 14 daysMcNicholl, 201432 168 10 Omeprazole

20 mg/12 h87 81%

Sequential, 10 daysMolina-Infante, 201526 375 14 Esomeprazole

40 mg/12 h90.4 81.3%

Triple, 14 daysCuadrado-Lavin, 201524 120 10 Omeprazole

20 mg/12 h90 90.8%

Hybrid, 10 days70%Triple, 10 days

Cosme, 201646 118 10 Omeprazole20 mg/12 h

87 94%Treatment guided byantibiotic sensitivitytesting, 10 days

McNicholl, 201533 630 14 Esomeprazole40 mg/12 h

91 87%Concomitant, 10 days

PPI: proton pump inhibitor.

Triple therapy (PPI, clarithromycin and amoxicillin)

The mean efficacy of triple therapy in Spain was 80% and70% in 2 systematic reviews published in 2011 and 2013,respectively.22,23 The efficacy of triple therapy in subsequentSpanish studies has always been less than 75%.24,25 A recentmulticentre study using triple therapy for 14 days with high-dose PPIs managed to increase efficacy to 81%.26 In Spain,the mean rate of resistance to clarithromycin was 14% in200927 and 18% in an updated review in 2013.23 A recentstudy has shown the rate of resistance to clarithromycinin children to be 34%,28 while in a multicentre study con-ducted in the Andalusia region of Spain, published in 2015,the mean rate of resistance was 18%.29 Together, all thisevidence points to the need to abandon triple therapy asfirst-line treatment in Spain, especially when therapeuticalternatives with significantly better cure rates are nowavailable; these include non-bismuth quadruple therapies(in sequential, concomitant or hybrid regimens), which willbe reviewed below.

Non-bismuth quadruple therapies (PPI, amoxicillin,clarithromycin and metronidazole)

The efficacy of non-bismuth quadruple therapies will dependon the prevalence of H. pylori strains that are simulta-neously resistant to clarithromycin and to metronidazole(dual or double resistance).21 Concomitant treatment isthe most effective quadruple therapy in situations of highresistance. Sequential, hybrid and concomitant treatmentsare estimated to achieve cure rates >90% when this dou-ble resistance rate is below 5%, 9% and 15%, respectively.In Spain, the dual resistance rate is still below 15%. Sev-eral studies conducted in Europe (Spain,24,26,30---33 Greece34---36

and Italy37,38) and Asia (Taiwan39,40 and Japan41) have shown

an efficacy close to or greater than 90% in intention-to-treat analysis. Nevertheless, in certain regions of Europeand Asia, with much higher rates of resistance to clar-ithromycin and metronidazole, the efficacy of concomitanttreatment has been suboptimal (Turkey,42 South Korea43,44

and China45). The outcomes obtained with this quadrupletreatment in various studies conducted in Spain since 2012are summarised in Table 3, showing a mean eradicationefficacy of approximately 90%.24,26,30---33,46 Quadruple conco-mitant treatment is therefore considered a valid first-choicealternative.

Several recent studies and meta-analyses have shownthat sequential therapy (PPI together with amoxicillin forthe first 5 days, followed by PPI together with clarithromycinand metronidazole for the last 5 days) is not superior to14-day triple therapy.47---50 Furthermore, concomitant treat-ment is significantly superior to sequential treatment whenboth are prescribed for a similar length of time.51 In addi-tion, suboptimal results with this regimen have recentlybeen published in our setting.32,52,53 Therefore, the use ofsequential therapy is not currently recommended.

Hybrid treatment (PPI together with amoxicillin for thefirst 5---7 days, followed by PPI together with amoxicillin,clarithromycin and metronidazole for the last 5---7 days) isa therapeutic alternative that reduces the antibiotic loadduring the first half of treatment, and could theoreticallyimprove tolerance and treatment compliance. This treat-ment showed an initial efficacy of 97% in a multicentrestudy conducted in Taiwan,54 later confirmed in 2 subse-quent Taiwanese studies, even with a duration less than14 days.55,56 Nevertheless, it is important to highlight thatthe clarithromycin resistance rate in Taiwan is low (8%).57

The efficacy of hybrid treatment was corroborated in laterstudies in Iran58,59 and Spain.24,31 The eradication rate inboth Spanish studies was 90%, with durations of 1024 and14 days.31 In contrast, recent studies published in Italy37,38


and Korea44,60 have shown hybrid treatment to be lesseffective (77---85%). Either way, a more robust comparativevalidation of this hybrid therapy is required before it can beincorporated into our therapeutic armamentarium.

In summary, a non-bismuth quadruple concomitantregimen is recommended as first-line treatment of H. pyloriinfection in Spain. The duration of therapy and dose ofeach component (i.e. PPI, clarithromycin, amoxicillin andmetronidazole) are summarised in Table 2. For furtherdetails on the duration of treatment, see recommendation4.

• Recommendation 3. Bismuth-containing quadrupletherapy (PPI, bismuth, tetracycline and metronidazole)could be an alternative first-line eradication treatmentonce its efficacy has been confirmed in our setting.

Agreement: 100%; votes: completely agree (92.3%);mostly agree (7.7%). GR: weak. CE: low.

Bismuth-containing quadruple therapy (PPI, bismuth,tetracycline and metronidazole) could be a valid alterna-tive to non-bismuth quadruple treatment, since it consistsof drugs such as bismuth and tetracycline, to whichH. pylori is never or only exceptionally resistant.61 In addi-tion, resistance to metronidazole may be partially overcomeby increasing the dose, frequency and duration of treatmentwith this antibiotic.61 In countries such as China, with ratesof resistance to clarithromycin of between 20% and 40%,and resistance to metronidazole greater than 60%, whereno triple or non-bismuth quadruple treatment will reachacceptable efficacy rates, bismuth-containing quadrupletherapies are currently the preferred first-line treatment.62

However, experience in Spain has been limited by the fre-quent lack of availability of tetracycline.

Three meta-analyses carried out in last decade have beenunanimous in stressing that bismuth-containing quadru-ple therapy (mean efficacy of 81%, 78% and 77%) has noadvantage over triple treatment.63---65 However, bismuth-containing quadruple therapy was prescribed for only 7 daysin the studies on which these meta-analyses were based,and moreover, they were published over a decade ago ormore, when clarithromycin resistance rates (which penalisethe efficacy of triple therapy) were considerably lower. Arecent European multicentre study showed good outcomeswith Pylera (a capsule containing bismuth, tetracyclineand metronidazole) administered for 10 days, reaching amodified intention-to-treat efficacy (confirmed by a singlebreath test) of 90% (significantly higher than that of tripletherapy).66 Nevertheless, there are some limitations anduncertainties surrounding this new pharmaceutical formu-lation (Pylera), such as: (1) it is available in a single 10-dayformat, when a 14-day course might increase its efficacyagainst metronidazole-resistant H. pylori67; (2) it includesrelatively low doses of tetracycline (2 g/day in the standardregimen versus 1.5 g/day in Pylera); (3) so far, there is verylittle experience---and therefore scientific evidence---for thisnew therapeutic formulation in the treatment of infectionin Spain, and (4) although Pylera will very likely improvetreatment compliance, it is not known whether it willaffect the onset of adverse effects.68 Furthermore, thereare no comparative studies between bismuth-containing and

non-bismuth (concomitant) quadruple therapies. The recentrelease of Pylera on the Spanish market (2016) should enableall these questions to be answered.

Finally, a new therapeutic approach is bismuth-containing quadruple treatment together with amoxicillinand metronidazole. These combinations have the advantageof using cheap and easily accessible antibiotics, dispensingwith tetracycline. The high efficacy of this new first-linetreatment regimen (close to or greater than 90%) has beendemonstrated in 2 recent studies conducted in China andThailand,68,69 both of which have a high rate of resistanceto clarithromycin (45% and 50%, respectively). It should benoted that the efficacy of this bismuth-containing quadrupletherapy against metronidazole-resistant strains was signi-ficantly reduced when used for less than 7 days (72%)69

compared to 14 days (>90%).68 Nevertheless, this promis-ing therapeutic regimen must be validated in Spain beforeit can be recommended.

In summary, bismuth-containing quadruple therapy(PPI, bismuth, tetracycline and metronidazole) could bean alternative first-line eradication treatment in Spain,once its efficacy has been confirmed in our setting. Theduration and dose of its components are summarised inTable 2. For further details on the duration of treatment,see recommendation 5.

• Recommendation 4. The recommended duration ofnon-bismuth quadruple concomitant therapy (PPI, clar-ithromycin, amoxicillin and metronidazole) is 14 days.

Agreement: 100%; votes: completely agree (85.7%);mostly agree (14.3%). GR: strong. CE: low.

Non-bismuth quadruple concomitant therapy, developedat the end of the 1990s, was initially designed to reduce theduration of eradication treatment.70 In fact, initial studiesfrom Germany and Japan suggested that a duration of 3---5 days could be sufficient to reach acceptable cure rates.71,72

More recently, however, various clinical trials comparingdifferent durations of this therapy have shown superiorcure rates with longer treatments: 3 days (81%) vs 5 days(89%)73; 5 days (87%) vs 7 days (90%)74; 5 days (89%) vs10 days (96%)75; or 5 days (78%) vs 14 days (86%).38 In arecent non-randomised Spanish study, concomitant treat-ment administered for 14 days (with high-dose PPI) wassuperior to another administered for 10 days (with standard-dose PPI; 87% vs 91%, p < 0.01).33 In line with this, the firstmeta-analysis of this therapy revealed that the efficacy ofconcomitant treatment was dependent on the duration, sothat the longer the course of treatment, the better theefficacy.76 Finally, this same tendency can be observed inthe overall experience in Spain in the last 4 years, whereonly 14-day treatments consistently exceeded the efficacythreshold of 90% (Table 3).

In summary, and as a general rule, it is currently rec-ommended that the duration of quadruple concomitanttreatment should be 14 days. Concomitant treatment willobtain cure rates greater than 90% in regions with dual resis-tance (clarithromycin and amoxicillin) rates <15%, as is thecase of Spain at present, provided that it is optimised interms of extended duration (14 days) (and possibly high-dosePPI).77


• Recommendation 5. The suggested duration of bismuth-containing quadruple therapy (PPI, bismuth, tetracyclineand metronidazole) is 10 or 14 days.

Agreement: 100%; votes: completely agree (100%). GR:weak. CE: low.

In a meta-analysis published in 2004 on different erad-ication treatments, the efficacy of bismuth-containingquadruple therapy administered for 1---3, 4 and 7 days wasobserved to be lower compared with a duration of 10---14days.78 Similarly, a duration of 10 days or more was foundto achieve cure rates greater than 85%, even in regions witha high prevalence of metronidazole resistance.78 However,a recent systematic review by the Cochrane Collaboration,which included 6 studies (1157 patients) with differentbismuth quadruple combinations, was unable to show a sig-nificant advantage for any treatment duration (7, 10 and 14days).79

To date, only one study (417 patients) has directlycompared 10- and 14-day bismuth-containing quadrupletherapy, finding no differences between regimens (91.6%vs 92.6%).80 In 2 large randomised clinical trials thatincluded a 10-day course of Pylera (the capsule containingbismuth, tetracycline and metronidazole), the intention-to-treat efficacy was 87.7%81 and 80%,66 being effective againstmetronidazole-resistant strains in 80% and 91% of cases,respectively. In a small pilot study that evaluated the effi-cacy of this same pharmaceutical formulation for 14 days,the intention-to-treat efficacy was 85.1%, although 100% ofthe metronidazole-resistant strains were eradicated.67 In allthese studies, the per-protocol efficacy was higher (91%,81

93%66 and 97%67) than the intention-to-treat efficacy, whichsuggests that poor compliance as a result of the relativelyhigh rate of adverse effects associated with this therapy(58%,81 47%66 and 74%67) is key to explaining these results,independent of the treatment duration.

A 10-day bismuth-containing quadruple treatment will behighly effective against strains sensitive to metronidazole,but it is likely that a 14-day treatment will be more effec-tive than a 10-day course against strains resistant to thisantibiotic.68 In this respect, 2 recent studies that evaluatednew quadruple treatments with bismuth combined with PPI,amoxicillin and metronidazole have shown cure rates >90%in China and Thailand, where resistance to metronidazole is45% and 50%, respectively69,82; however, the efficacy of thisnew treatment against metronidazole-resistant strains wassignificantly reduced in shorter treatments: 7 days (72%)82

vs 14 days (>90%).69 This should be taken into account inSpain, where the mean rate of resistance to metronidazoleis currently 41% (30---47%).23 Experience in our setting withfirst-line bismuth-containing quadruple therapy has beenlimited by the frequent shortage of tetracyclines. Therecent release of Pylera in Spain will allow us to determinewhether this treatment is sufficiently effective when usedfor 10 days (the only format currently available), or if itwill need to be prolonged. Comparative studies evaluatingthe efficacy, safety and cost of different regimens areneeded to clarify the ideal duration of bismuth-containingquadruple therapy. Meanwhile, it seems prudent to suggestthat the duration of this therapy should be at least 10 days.

• Recommendation 6. A bismuth-containing quadrupleregimen (PPI, bismuth, tetracycline and metronidazole) isrecommended as first-line treatment in patients allergic topenicillin.

Agreement: 100%; votes: completely agree (100%). GR:strong. CE: low.

Amoxicillin is one of the most effective antimicrobialagents against H. pylori and, therefore, most eradicationtreatments include this antibiotic. Experience with eradica-tion treatment in patients allergic to penicillin has been veryscant to date, although this allergy is relatively common inclinical practice.

Triple therapy with PPI, clarithromycin and metron-idazole is generally recommended in patients allergic tobeta-lactamics.18 In a meta-analysis performed 15 yearsago, treatment with PPI, clarithromycin and nitroimidazolewas considered relatively effective for the treatment ofH. pylori infection, with mean eradication rates above80%.83 In an initial Spanish prospective study, this regimenwas administered for 7 days to 12 patients who were allergicto penicillin, but obtained an eradication rate (intention-to-treat analysis) of only 58%.54 In another subsequent Spanishstudy---in this case multicentre---eradication rates as low as55% were obtained when the same treatment was used in50 patients.85 The disappointing cure rates (<60%) in theaforementioned recent Spanish studies84,85 could be due, atleast in part, to the increase in rates of resistance to bothclarithromycin and to metronidazole.23,27,86

In contrast, 2 groups of investigators evaluated theefficacy of a 10-day regimen with PPI, tetracycline andmetronidazole in 5 and 17 patients allergic to peni-cillin, obtaining intention-to-treat eradication rates of80---85%.87,88 These encouraging results suggest that thistriple combination (or better still, with the addition of bis-muth, which would result in a quadruple regimen) could bea better alternative first-line treatment in patients aller-gic to penicillin (mainly in areas with high resistance tometronidazole or clarithromycin). This is probably becausethe negative effect of the metronidazole resistance is over-come by the co-administration of bismuth,89 and becausethe efficacy of this regimen is not affected by resistance toclarithromycin.66

In this respect, the findings of a Spanish prospectivemulticentre study were recently updated. In this case,267 patients allergic to penicillin were given first-linetreatment with omeprazole, clarithromycin and metronida-zole for 7 days, or omeprazole, bismuth, tetracycline andmetronidazole for 10 days.90 The intention-to-treat erad-ication rate with the triple therapy was only 57%, whilethat of the quadruple regimen was clearly higher (74%).Treatment compliance was 94% and 98%, respectively. Four-teen percent of patients reported adverse effects withboth regimens (all mild). The authors therefore concludedthat, although a triple combination with PPI, clarithromycinand metronidazole can be prescribed to patients allergicto penicillin in areas with low clarithromycin resistance,standard bismuth-containing quadruple therapy should bepreferred in countries such as Spain, where resistance toclarithromycin is common.


Finally, Liang et al.91 randomised 109 penicillin-allergicpatients to receive standard bismuth-containing quadru-ple therapy (PPI, bismuth, tetracycline and metronidazole)for 2 weeks, or a modified bismuth-containing quadru-ple regimen (PPI, bismuth, tetracycline and furazolidone).The intention-to-treat eradication rates were, respectively,88% and 92%, supporting the effectiveness of the bismuth-containing regimens in patients allergic to penicillin.

In summary, bismuth-containing quadruple therapy (PPI,bismuth, tetracycline and metronidazole) is recommendedin Spain as first-line treatment in patients allergic topenicillin.

• Recommendation 7. Probiotics should not be indiscrim-inately combined with eradication treatment.

Agreement: 100%; votes: completely agree (85.7%);mostly agree (7.1%); somewhat agree (7.1%). GR: strong.CE: low.

Probiotics are live microorganisms that, when admin-istered in adequate amounts, may be beneficial tohealth; they are currently indicated in the treatment ofacute gastroenteritis and antibiotic-induced diarrhoea.92

The microorganisms most commonly used in probioticformulations in clinical practice are Lactobacillus spp.,Bifidobacterium and Saccharomyces, as well as Bacillus,Streptococcus and Escherichia coli. Their potential benefi-cial effects include regulation of the intestinal microbiota,stimulation of the immune system response and potentialinhibitory activity against H. pylori demonstrated in vivo andin vitro.93

There is strong scientific evidence synthesised innumerous meta-analyses on the use of numerous differ-ent probiotic formulations (Lactobacillus combined withBifidobacterium, bovine lactoferrin, lactic ferment, Saccha-romyces boulardii and other probiotic formulations) thatoverall suggest a reduction in adverse effects and, to alesser degree, an improvement the cure rate of eradica-tion treatments.94---104 However, negative findings associatedwith probiotics combined with triple therapy have beenreported.105---107 These discordant results are likely relatedwith the use of different strains and combinations of strains,as well as different concentrations, doses and duration oftreatment.77,108 Moreover, the immense majority of stud-ies on probiotics have evaluated their impact on standardtriple therapy, a well-tolerated treatment that is not recom-mended as first-line treatment due to insufficient efficacy.A recent meta-analysis that included 33 clinical trials and4459 patients showed that the therapeutic gain obtainedwith probiotics was greater the less effective the erad-ication treatment.102 In fact, probiotic supplementationprovided no therapeutic benefit when the effectivenessof eradication treatment was greater than 80%. No stud-ies have yet been published evaluating the usefulness ofprobiotics combined with quadruple concomitant therapy,which is currently the recommended first-line treatment inSpain.

It should also be noted that probiotics are not subsidisedin Spain, which increases the costs of eradication treatment;furthermore, the addition of a fifth drug adds to the com-plexity of quadruple treatment. Finally, no studies have as

yet identified predictive risk factors for side effects withantibiotic therapy, and therefore administration of probi-otics cannot be individualised. Probiotics can be consideredin very specific cases, such as in patients with poor toleranceto or side effects with previous antibiotic treatments.

In conclusion, more evidence on the impact of probioticson the effectiveness and safety of the new quadruple H.pylori eradication treatments is needed before they can beimplemented in routine clinical practice. For now, there-fore, probiotics should not be indiscriminately combinedwith eradication treatment.

• Recommendation 8. Following failure of a first treat-ment that includes clarithromycin (triple or quadruple) aregimen, preferably quadruple, that includes levofloxacin isrecommended (PPI, amoxicillin, levofloxacin and bismuth).Another alternative is bismuth-containing quadruple ther-apy (PPI, bismuth, tetracycline and metronidazole).

Agreement: 100%; votes: completely agree (76.9%);mostly agree (15.4%); somewhat agree (7.7%). GR: strong.CE: moderate (after failure of triple therapy); low (afterfailure of quadruple therapy).

After failure of triple therapy

After failure of triple therapy with PPI, clarithromycin andamoxicillin, it is reasonable to assume that H. pylori wasalready resistant to clarithromycin (primary resistance) orthat it has developed resistance (secondary) to this antibi-otic after failed eradication treatment; therefore, re-useof this antibiotic should be avoided. In this respect, acombined analysis of 8 studies found a very low eradica-tion rate (46%) when clarithromycin-containing therapy wasrepeated.109

When standard triple treatment (PPI, clarithromycinand amoxicillin; combination currently not recommended)has failed, standard quadruple therapy (PPI, bismuth,tetracycline and metronidazole) has traditionally been rec-ommended. The results obtained with this strategy aresummarised in Fig. 2 (mean eradication rate of 78%).109

Given the complexity of bismuth-containing quadrupletherapy and the shortage of tetracycline and bismuth saltsin many countries, several studies have recently been con-ducted using levofloxacin as rescue treatment. The resultshave been encouraging, as summarised in Fig. 3 (mean erad-ication rate of 76%). Three meta-analyses have compareda levofloxacin-containing triple regimen against a bismuth-containing quadruple therapy as second-line treatment, andhave shown better efficacy and a lower rate of adverseeffects with the levofloxacin-containing triple therapy.110,111

These meta-analyses have recently been updated to include13 studies with a total of 1709 patients (1011 withlevofloxacin-containing triple treatment and 698 with bis-muth quadruple therapy).109 This meta-analysis showeda non-statistically significant tendency towards highereradication efficacy of the levofloxacin-containing tripletreatment compared to the bismuth-containing quadrupletherapy (79% vs 70%; odds ratio [OR] = 1.43; 95% confidenceinterval [95% CI] = 0.88---2.31), with a significantly lower rate


Boixeda et al. 2002

Study Eradication rateWeightSEEradication rate

IV, random, 95% CI

Eradication rate

IV, random, 95% CI

0.82142857

Cheon et al. 2006

Cheon et al. 2006b

Choung et al. 2004

Chung et al. 2007

Chung et al. 2009

Chung et al. 2011

Chung et al. 2012

Elizalde et al. 1998

Finizio et al. 2005

Franceschi et al. 2011

Georgopoulos et al. 2002

Gisbert et al. 1999

Gisbert et al. 2008

Gomollon et al. 1999

Kang et al. 2006

Kang et al. 2007

Kim et al. 2003

Kuo et al. 2009

Kuo et al. 2010

Lee et al. 2010

Magaret et al. 2001

Mantzaris et al. 2005

Marko et al. 2005

Michopoulos et al. 2000

Michopoulos et al. 2012

Moon et al. 2012

Nista et al. 2003

Nista et al. 2004

Ozcay et al. 2004

Park et al. 2004

Peitz et al. 1998

Perri et al. 2003

Rokkas et al. 2009

Sicilia et al. 2000

Uygun et al. 2008

Wu et al. 2006

Wu et al. 2011

0.65517241

0.54545455

0.83098592

0.83908046

0.87771203

0.83417085

0.78378378

0.87096774

0.68

0.7

0.89673469

0.77777778

0.55263158

0.95238095

0.9

0.71698113

0.91489362

0.63855422

0.75789474

0.73568282

0.75

0.73043478

0.62962963

0.76315789

0.75555556

0.84210526

0.62857143

0.71428571

0.9375

0.96261682

0.5862069

0.75384615

0.69166667

0.86363636

0.78

0.76595745

0.80645161

3.3%

1.9%

2.2%

3.0%

3.1%

3.6%

3.4%

2.4%

2.6%

2.4%

2.5%

2.8%

1.1%

2.1%

2.9%

2.7%

2.5%

3.4%

2.8%

3.3%

3.4%

0.3%

3.1%

1.8%

2.3%

2.5%

2.9%

2.6%

2.2%

2.6%

3.6%

1.8%

3.2%

3.1%

2.2%

3.1%

2.5%

2.8%

0.50–0.5–1 1

0.03236882

0.08826323

0.07506571

0.04447635

0.0393955

0.01455003

0.02636522

0.06767705

0.0602101

0.06596969

0.06480741

0.05280108

0.1385799

0.08066009

0.04647143

0.05477226

0.0618762

0.02878077

0.05273287

0.03107633

0.02926814

0.30618622

0.0413784

0.0929349

0.06896756

0.06406444

0.04829805

0.05775186

0.07636035

0.06051536

0.01833889

0.09145724

0.03778096

0.04215684

0.073165

0.04142463

0.06175908

0.05017508

0.82 [0.76, 0.88]

0.66 [0.48, 0.83]

0.55 [0.40, 0.69]

0.83 [0.74, 0.92]

0.84 [0.76, 0.92]

0.88 [0.85, 0.91]

0.83 [0.78, 0.89]

0.78 [0.65, 0.92]

0.87 [0.75, 0.99]

0.68 [0.55, 0.81]

0.70 [0.57, 0.83]

0.84 [0.73, 0.94]

0.78 [0.51, 1.05]

0.55 [0.39, 0.71]

0.95 [0.86, 1.04]

0.90 [0.79, 1.01]

0.72 [0.60, 0.84]

0.91 [0.86, 0.97]

0.64 [0.54, 0.74]

0.76 [0.70, 0.82]

0.74 [0.68, 0.79]

0.75 [0.15, 1.35]

0.73 [0.65, 0.81]

0.63 [0.45, 0.81]

0.76 [0.63, 0.90]

0.76 [0.63, 0.88]

0.84 [0.75, 0.94]

0.63 [0.52, 0.74]

0.71 [0.56, 0.86]

0.94 [0.82, 1.06]

0.96 [0.93, 1.00]

0.59 [0.41, 0.77]

0.75 [0.68, 0.83]

0.69 [0.61, 0.77]

0.86 [0.72, 1.01]

0.78 [0.70, 0.86]

0.77 [0.64, 0.89]

0.81 [0.71, 0.90]

100.0%CI)Total (95% 0.78 [0.75, 0.81]

Heterogeneity: Tau2 =0.01; Chi

2 =208.49, df=37 (P<.00001); I

2 =82%

Test for overall effect: Z=44.91 (P<.00001)

Figure 2 Efficacy (intention-to-treat) of second-line bismuth-containing quadruple therapy (PPI, bismuth, tetracycline andmetronidazole) after failure of triple treatment with PPI, amoxicillin and clarithromycin.

of adverse effects (14% vs 32%; OR = 0.30; 95% CI = 0.19---0.50)and serious adverse effects (0.7% vs 7.8%; OR = 0.15; 95%CI = 0.04---0.59). Ten-day levofloxacin-containing triple ther-apy was more effective than the 7-day course (89% vs70%). Finally, a sub-analysis that included only studies thatadministrated a triple regimen with PPI, levofloxacin andamoxicillin for 10 days showed that this is more effectivethan a bismuth-containing quadruple therapy (89% vs 66%;OR = 4.22; 95% CI = 2.84---6.26).

These promising results with levofloxacin have recentlybeen confirmed in a large Spanish multicentre study, inwhich 1000 patients in whom first-line eradication treat-ment with PPI, amoxicillin and clarithromycin had failedreceived PPI, amoxicillin and levofloxacin for 10 days.112

Eradication was achieved in 74% of patients, and althoughadverse effects were described in one fifth of cases, noneof these was serious. This study also assessed whether effi-cacy diminished over time, since resistance to quinolones inSpain appears to be rising rapidly. However, the eradicationrates remained stable over the 6 years of the study.112

Nevertheless, the efficacy of levofloxacin-containingtriple therapy can evidently be improved (remember thatour current therapeutic objective is to reach an eradica-tion efficacy greater than or equal to 90% and we will notsettle for lower rates in either initial or rescue treatment).Moreover, as mentioned, the rate of resistance to quinolonesis increasing relatively fast, which could negatively impactthe efficacy of triple therapy. It has been suggested thatthis negative effect could be reduced with the addition ofbismuth. In this respect, a recent study has shown that theaddition of bismuth (PPI, amoxicillin, levofloxacin and bis-muth for 14 days) obtains a per-protocol eradication efficacyof 95%.113 The intention-to-treat efficacy was also high: 88%.These figures were higher than those obtained with (stan-dard) triple treatment with PPI, amoxicillin and levofloxacin(without bismuth). These favourable results were obtaineddespite a high rate of resistance to quinolones (30%), higherthan that described in our setting. This quadruple treat-ment (PPI, amoxicillin, levofloxacin and bismuth) achievederadication in 98% of patients with quinolone-sensitive


0.78 [0.68, 0.88]

0.38 [0.22, 0.53]

0.73 [0.58, 0.89]

0.82 [0.75, 0.90]

0.80 [0.75, 0.84]

0.68 [0.55, 0.81]

0.77 [0.73, 0.82]

0.74 [0.71, 0.77]

0.76 [0.63, 0.88]

0.70 [0.60, 0.80]

0.91 [0.86, 0.97]

0.77 [0.61, 0.93]

0.70 [0.54, 0.86]

0.83 [0.66, 1.01]

0.94 [0.89, 1.00]

0.87 [0.75, 0.99]

0.63 [0.51, 0.76]

0.70 [0.54, 0.85]

0.77 [0.68, 0.86]

–0.5–1 0 0.5 1

5.5%

4.0%

3.9%

6.2%

6.9%

4.7%

6.9%

7.3%

4.8%

5.5%

6.8%

3.9%

3.8%

3.6%

6.8%

4.9%

4.9%

4.0%

5.8%

0.05167483

0.07973066

0.08073734

0.0389611

0.0232371

0.06596969

0.02417222

0.01390525

0.06406444

0.05035781

0.02731951

0.08262864

0.083666

0.08784105

0.02774309

0.06206329

0.0622123

0.08000056

0.04555534

0.78125

0.37837838

0.73333333

0.82291667

0.79666667

0.68

0.77333333

0.738

0.75555556

0.69879518

0.91428571

0.76923077

0.7

0.83333333

0.94285714

0.86666667

0.63333333

0.6969697

0.76744186

Chuah et al. 2012

Study SE Eradication rate Weight Eradication rate

IV, random, 95% CI

Eradication rate

IV, random, 95% CI

Ermis et al. 2011

Festa et al. 2002

Finizio et al. 2005

Franceschi et al. 2011

Gisbert et al. 2007

Gisbert et al. 2008

Gisbert et al. 2012

Hu et al. 2011

Kuo et al. 2009

Lee et al. 2006

Liou et al. 2010

Matsumoto et al. 2005

Nista et al. 2002

Nista et al. 2003

Nista et al. 2004

Perri et al. 2003

Watanabe et al. 2003

Zullo et al. 2010

Total (95% CI) 100.0% 0.76 [0.72, 0.81]

Heterogeneity: Tau2=0.01; Chi

2 =110.09, df=18 (P<.00001); I

2 =84%


Figure 3 Efficacy (intention-to-treat) of a second-line triple treatment with PPI, amoxicillin and levofloxacin after failure of tripletherapy with PPI, amoxicillin and clarithromycin.

H. pylori strains and, more importantly, achieved eradica-tion in a relatively high percentage (71%) of levofloxacin-resistant strains. However, when the standard levofloxacin-containing triple treatment was used, the infection wasonly eradicated in 38% of patients with quinolone-resistantstrains.

Several studies have evaluated this levofloxacin-containing quadruple therapy (PPI, amoxicillin, levofloxacinand bismuth) as second-line treatment, as shown inTable 4, and have reported satisfactory eradication ratesin general.113---118 Among these, a recent Spanish mul-ticentre study administered a quadruple combinationwith esomeprazole (40 mg/12 h), amoxicillin (1 g/12 h),levofloxacin (500 mg/24 h) and bismuth (240 mg/12 h) for14 days to 200 patients in whom triple (PPI, clarithromycinand amoxicillin) or non-bismuth quadruple therapy hadpreviously failed.118 Ninety-six percent of the patientstook the medication correctly. Overall, the per-protocoland intention-to-treat eradication rates were 91.1% and90%, respectively. The figures were similar, regardless ofthe previous treatment. Almost half the patients (46%)presented adverse effects, but only 3% were classified asintense, and none was serious. The authors therefore con-cluded that a 14-day bismuth- and levofloxacin-containingquadruple therapy was a simple, safe and effective (≥90%cure) second-line therapy in patients with failure of tripleeradication treatment. Nevertheless, it should be notedthat estimates suggest that this treatment will fail to reachacceptable eradication rates (≥90%) if the proportion oflevofloxacin-resistant H. pylori strains is >25%.119 In Spain,the most recently published studies report levofloxacinresistance rates of 15% in Cantabria,120 27% in Caceres31 and13% in an Andalusian multicentre study,29 so the increase inquinolone resistance rates should be monitored locally.

Finally, it should be noted that a small study recentlyevaluated, for the first time, the efficacy of Pylera (whichsimplifies the administration of bismuth-containing quadru-ple therapy) in 49 patients with failure of one or moreeradication treatments.121 The vast majority of patientshad received one or several treatments with omeprazole,clarithromycin and amoxicillin; H. pylori was resistant toclarithromycin in 31 of the 49 (63%) patients. The 10-dayPylera treatment managed to eradicate H. pylori in 93% and95% of patients in the intention-to-treat and per-protocolanalysis, respectively.

After failure of non-bismuth quadrupletherapy

Non-bismuth quadruple therapies that include PPI, amox-icillin, clarithromycin and a nitroimidazole (especially ina concomitant regimen) are increasingly used as first-linetreatment. It is a challenge to find rescue treatments fol-lowing the failure of these therapies that use key antibioticssuch as clarithromycin and nitroimidazoles.

For the present consensus, a systematic review withmeta-analysis was performed to evaluate which second-linetreatments have been investigated after a failed attempt toeradicate H. pylori infection with these therapies. Studieswere selected if they evaluated the efficacy of second-line regimens after the failure of first-line therapies suchas sequential, concomitant or hybrid regimens. Studies inwhich the second-line treatment was chosen according toantibiotic sensitivity, or which lacked a detailed descriptionof the composition of the therapies (administered as first-line or rescue) were excluded. The data were synthesisedby intention-to-treat eradication rate and, when possible,


Table 4 Studies that evaluated the efficacy (intention-to-treat) of the combination of PPI, amoxicillin, levofloxacin and bismuthfor the eradication of Helicobacter pylori infection.

Author and year of publication Country Treatment line Duration (days) Eradication n/No. (%)

Bago, 2007114 Croatia First 7 57/66 (86)Gao, 2010115 China First 10 60/72 (83)Gisbert, 2015118 Spain Second 14 180/200 (90)Hsu, 2008116 Taiwan Third 10 31/37 (84)Liao, 2013113 China First 14 70/80 (87.5)Yee, 2007117 China ≥Second 7 37/51 (73)

PPI: proton pump inhibitor.

Studya

b

c

WeightSEEradication rate

Eradication rate

IV, Random, 95% CI

Eradication rate

IV, Random, 95% CI

Study WeightSEEradication rateEradication rate

IV, Random, 95% CI

Eradication rate

IV, Random, 95% CI

Study WeightSEEradication rateEradication rate

IV, Random, 95% CI

Eradication rate

IV, Random, 95% CI

0.94 [0.77, 1.11]15.4%0.085581650.9375Georgopoulos et al 2013

0.74 [0.65, 0.82]

0.71 [0.49, 0.92]

0.50 [0.10, 0.90]

0.93 [0.74, 1.12]

0.86 [0.74, 0.97]

0.56 [0.33, 0.79]

0 0.5 1

23.2%

11.8%

5.0%

13.6%

20.0%

11.1%

0.04200998

0.11051017

0.20412415

0.09734073

0.05914848

0.11712139

0.73636364

0.70588235

0.5

0.92857143

0.85714286

0.55555556

Gisbert et al 2014

Manfredi et al 2012

Perna et al 2007

Pontone et al 2010

Zullo et al 2006

Zullo et al 2013

Gisbert et al 2014 0.064388320.81081081 0.81 [0.68, 0.94]29.7%

0.71 [0.49, 0.92]

0.50 [0.10, 0.90]

0.93 [0.74, 1.12]

0.86 [0.74, 0.97]

0.60 [0.17, 1.03]

13.0%

4.3%

16.1%

33.1%

3.7%

0.11051017

0.20412415

0.09734073

0.05914848

0.21908902

0.70588235

0.5

0.92857143

0. 85714286

0.6

Manfredi et al 2012

Perna et al 2007

Pontone et al 2010

Zullo et al 2006

Zullo et al 2013

38.5%0.085581650.9375Georgopoulos et al 2013 0.94 [0.77, 1.11]

0.70 [0.59, 0.80]

0.60 [0.17, 1.03]

46.6%

14.8%

0.05370468

0.21908902

0.69863014

0.6

Gisbert et al 2014

Zullo et al 2013

Total (95% CI) 100.0% 0.78 [0.68, 0.88]


2 =14.48, df=8 (P=.02); I

2=59%

Test for ov erall effec t: Z=1 5.5 4 (P<. 000 01)

0 0.5 1

0 0.5 1

Total (95% CI) 100.0% 0.81 [0.73, 0.90]


2=6.19, df=5 (P=0.29); I

2=19%

Test for ov erall effec t: Z=1 8.7 2 (P <.00001 )

Total (95% CI) 100.0% 0.78 [0.58, 0.97]

Heterogeneity: Tau2=0.02; Chi

2 =6.14, df=2 (P=.05,); I

2=67%

Test for ov erall effec t: Z=7 .83 (P<.0 000 1)

Figure 4 (a) Efficacy (intention to treat) of a second-line treatment with PPI, amoxicillin and levofloxacin after failure of anon-bismuth quadruple therapy (sequential or concomitant). (b) Efficacy (intention-to-treat) of a second-line treatment with PPI,amoxicillin and levofloxacin after failure of a sequential therapy. (c) Efficacy (intention-to-treat) of a second-line treatment withPPI, amoxicillin and levofloxacin after failure of a concomitant therapy.

meta-analyses were performed using the inverse variancemethod.

Sixteen studies were selected using this strategy: 7included patients in whom concomitant treatment hadfailed, 15 in whom sequential treatment had failed, and1 in whom hybrid treatment had failed. Most of thestudies evaluated a rescue therapy with PPI, amoxicillin

and levofloxacin, a combination that obtained an overalleradication rate of 78% following failure of non-bismuthquadruple therapy (Fig. 4a).36,37,122---126 The rescue regimenwas administered for 10 days in all the studies, and inall except one,122 250 mg of levofloxacin was prescribedtwice daily. This triple therapy (PPI, amoxicillin and lev-ofloxacin) was effective after failure of both sequential


(81%) (Fig. 4b)37,122---126 and concomitant treatment (78%)(Fig. 4c).36,37,122 Only 1 study37 evaluated the results oflevofloxacin-containing triple therapy after the failure ofhybrid therapy, with a 50% cure rate. Tolerance to this rescueregimen was generally good.

Some authors have used moxifloxacin instead of lev-ofloxacin in this triple rescue regimen (i.e. PPI, amoxicillinand moxifloxacin); the mean eradication rate was 71%(238 patients) after the failure of non-bismuth quadrupletherapies.127---129 These results should be interpreted withcaution, due to the high heterogeneity of the studies and thedifferences in the study characteristics (e.g. the durationand dose of moxifloxacin were different in each study).

As previously mentioned, an important aspect oflevofloxacin-containing therapy is that it is less effectivein the presence of resistance to fluoroquinolones.130 Thus,recent studies suggest that the efficacy of levofloxacin-containing triple therapy is decreasing, probably due to theincrease in these resistances.131 Similarly, bismuth seemsto have a synergic effect with certain antibiotics and toovercome resistance to clarithromycin and levofloxacin toa large extent.113,132 Accordingly, some authors have evalu-ated a quadruple regimen adding bismuth to levofloxacin(i.e. PPI, amoxicillin, levofloxacin and bismuth), obtain-ing encouraging results.113---118 A recent Spanish multicentrestudy evaluated the efficacy of a quadruple combinationwith PPI, amoxicillin, levofloxacin and bismuth for 14 days in200 patients in whom triple or non-bismuth quadruple ther-apy (either sequential or concomitant) had previously failed,obtaining per-protocol and intention-to-treat eradicationrates of 91.1% and 90%, respectively.118 These figures weresimilar, regardless of the previous treatment: triple therapy88.5% vs sequential 93.8% vs concomitant 91.9%. Therefore,14-day bismuth- and levofloxacin-containing quadruple ther-apy is an effective second-line therapy (≥90% cure) notonly in patients following failure of standard triple ther-apy, but also in those with failure of quadruple sequential orconcomitant therapy; the results are even better than thosedescribed with levofloxacin-containing triple therapy.

Only 2 studies to date (both with small sample sizes) haveevaluated the efficacy of standard quadruple therapy (PPI,bismuth, tetracycline and metronidazole) following the fail-ure of a non-bismuth quadruple therapy (sequential in bothcases) (Fig. 5). In the first, the infection was eradicated in 8patients (100%) treated with a bismuth-containing quadru-ple therapy for 10 days133; in the second, the infection waseradicated in 10 of 14 patients (71%) treated for 14 days.134

There is very little evidence on other treatment options.Hsu et al.135 evaluated a modified bismuth-containingquadruple therapy (administering levofloxacin instead ofmetronidazole) after failure of the sequential regimen,obtaining an eradication rate of 96%. Fakheri et al.136 eval-uated a hybrid therapy with pantoprazole, amoxicillin andbismuth subcitrate for 14 days following failure of a sequen-tial regimen, adding furazolidone for the first week only;the infection was eradicated in 81% of patients. Finally, Liouet al.137 analysed the efficacy of a modified sequential ther-apy administered for 14 days (lansoprazole and amoxicillinadministered for the first 7 days, followed by lansoprazole,metronidazole and levofloxacin for a further 7 days) fol-lowing failure of the sequential treatment, achieving aneradication rate of 80%.

In summary, triple therapy with PPI, amoxicillin andlevofloxacin was the most widely evaluated rescue reg-imen after failure of non-bismuth quadruple therapies,reaching eradication rates close to 80%. More recently,bismuth has been considered as a valuable adjuvant inlevofloxacin-containing triple therapy; therefore, quadru-ple therapy (PPI, amoxicillin, levofloxacin and bismuth)may be considered preferable to triple therapy as res-cue therapy, although experience with this regimen isstill limited. Finally, bismuth-containing quadruple ther-apy (PPI, bismuth, tetracycline and metronidazole) hasobtained encouraging results as rescue treatment, but aspreviously mentioned, has only been evaluated in 2 smallstudies.

• Recommendation 9. Following failure of a first treat-ment with a bismuth-containing quadruple regimen (PPI,bismuth, tetracycline and metronidazole), a levofloxacin-containing triple or quadruple regimen is recommended(PPI, amoxicillin, levofloxacin ± bismuth).


Following failure of a bismuth-containing quadruple ther-apy, any treatment can theoretically be used, includingrepetition of the same bismuth-containing quadruple ther-apy, since the rate of acquired resistance following the useof amoxicillin, bismuth or tetracycline is insignificant (<3%)and resistance to metronidazole can be partially overcomewith higher doses and longer duration of the antibiotic.21

Nevertheless, it does not appear logical to repeat treat-ment that has already failed. It also seems reasonable toassume that bismuth-containing quadruple treatment wasused as a first option due to the high rate of clarithromycinresistance (which reduces the efficacy of triple therapy) anddual clarithromycin and metronidazole resistance (which isassociated with lower efficacy of non-bismuth quadrupletherapies).21

Experience after failure of bismuth-containing quadru-ple therapy is very scant. In this context, the MaastrichtIV consensus recommended the use of a levofloxacin-containing triple regimen.18 Studies that have evaluatedthe efficacy of a third-line treatment combining PPI,amoxicillin and levofloxacin for H. pylori eradicationfollowing the failure of 2 treatments, the second-linetreatment being the bismuth-containing quadruple regi-men, are summarised in Table 5 (efficacy between 60%and 85%).138---142

Very recently, a Korean study carried out in 28 patientsshowed that moxifloxacin-containing triple therapyachieved an eradication rate of 67% as second-linetreatment following the failure of a bismuth-containingquadruple treatment.128

In a study conducted in China, bismuth-containing ther-apy was effective as first-line treatment in 99% of patients,and in the 2 patients in whom it failed, sequential ther-apy (PPI and amoxicillin, followed by PPI, clarithromycinand metronidazole) was effective.133 However, the use ofa second-line clarithromycin-containing treatment follow-ing failure of a bismuth-containing quadruple therapy doesnot generally seem to be useful in clinical practice, as


Kim et al 2010

Study Eradication rate WeightSEEradication rate

IV, Random, 95% Cl

Eradication rate

IV, Random, 95% Cl

42.7%0.120736320.71428571

57.3% 0.94 [0.77, 1.11]

0.71 [0.48, 0.95]

0.085581650.9375Liu et al 2014

0.50 1

Total (95% CI) 100.0% 0.84 [0.63, 1.06]


2 =2.27, df=1 (P=.13); I

2 =56%


Figure 5 Efficacy (intention-to-treat) of a second line bismuth-containing quadruple therapy (PPI, bismuth, tetracycline andmetronidazole) after failure of a sequential therapy.

Table 5 Studies that evaluated the efficacy (intention-to-treat) of a third-line combination with PPI, amoxicillin and lev-ofloxacin for the eradication of Helicobacter pylori infection after 2 eradication failures.

Author and year of publication Patients (n) Previous treatments(failed)

Duration (days) Eradication (%)

Gatta, 2005138 151 (1st) PPI + C + A or M(2nd) PPI + C + A or M; Q

76

Gisbert, 2006139 100 (1st) PPI + C + A(2nd) Q

10 60


10 85

Rokkas, 2009141 30 (1st) PPI + C + A(2nd) Q

10 70


10 68

A: amoxicillin; C: clarithromycin; PPI: proton pump inhibitor; M: metronidazole; Q: bismuth-containing quadruple therapy (PPI, bismuth,tetracycline and metronidazole).

this bismuth-containing quadruple therapy is usually rec-ommended as first-line treatment precisely because of highresistance to clarithromycin in some areas. In contrast,it is well known that levofloxacin-containing triple ther-apy is effective as second-line treatment after failure of atherapy containing clarithromycin110,111,143; therefore, thiswould seem more advisable after failure of a bismuth-containing quadruple regimen.

Finally, as previously mentioned (see section on res-cue treatment following failure of triple or non-bismuthquadruple therapy), the addition of bismuth to levofloxacin-containing triple therapy has achieved promising results;the efficacy of this combination (PPI, amoxicillin, lev-ofloxacin and bismuth) as rescue treatment following thefailure of bismuth-containing quadruple therapy should beevaluated in the future.

• Recommendation 10. Rescue treatment in penicillin-allergic patients:

(a) After failure of a first triple treatment (PPI, clar-ithromycin and metronidazole), bismuth-containingquadruple therapy (PPI, bismuth, tetracycline andmetronidazole) is suggested.

(b) After failure of a first bismuth-containing quadrupletreatment, triple therapy with PPI, levofloxacin andclarithromycin is suggested.

Agreement: 100%; votes: completely agree (100%). GR:weak. CE: very low.

The eradication of H. pylori in penicillin-allergic patientsis a challenge, especially in those in whom a previous erad-ication attempt has failed. In a Spanish pilot study, 15patients allergic to penicillin in whom a first treatment withPPI, clarithromycin and metronidazole had failed received asecond treatment with PPI, clarithromycin and levofloxacinfor 10 days.85 Compliance was total in all cases. Adverseeffects were described in 20% of patients, all mild. Theeradication rate (intention-to-treat) was 73%.

More recently, in a Spanish multicentre study, 267penicillin-allergic patients received a first-line treat-ment with PPI, clarithromycin and metronidazole orbismuth-containing quadruple therapy (PPI, bismuth, tetra-cycline and metronidazole), and as rescue treatments,a bismuth-containing quadruple therapy or regimen withPPI, clarithromycin and levofloxacin for 10 days.90 Theintention-to-treat eradication rate with PPI, clarithromycinand levofloxacin was 64%, after failure of both first-line PPI,clarithromycin and metronidazole and bismuth-containingquadruple therapy, and compliance was 88---100%, with23---29% adverse effects (all mild). The authors thereforeconcluded that triple treatment with PPI, clarithromycinand levofloxacin is an alternative second-line treatment inpatients allergic to penicillin. The possibility of increasingthe efficacy of the latter combination by optimising thePPI dose and duration of treatment, or by adding bismuth,should be explored in the future.


Liang et al.91 randomised 109 penicillin-allergic patients(in most of whom PPI, clarithromycin and metronidazolehad failed) to receive standard bismuth-containing quadru-ple therapy (PPI, bismuth, tetracycline and metronidazole)for 2 weeks, or a modified bismuth-containing quadrupleregimen (PPI, bismuth, tetracycline and furazolidone; thelatter antibiotic is not available in Spain). The intention-to-treat and per-protocol eradication rates were 88% and 92%,respectively.

In a retrospective study, Furuta et al.144 treated28 patients allergic to penicillin with PPI, metronidazoleand sitafloxacin for 1 or 2 weeks, achieving H. pylori erad-ication in all patients. These encouraging results wereobtained despite a high rate of resistance to levofloxacin(60%), and could be explained by the fact that the mini-mum inhibitory concentration (MIC) of sitafloxacin is lowerthan that of levofloxacin, and could be effective in patientsinfected by strains with mutations in the gyrA genes (agenetic marker of levofloxacin resistance).145 However, inthis study, the sitafloxacin MICs were not determined and,therefore, the prevalence of strains resistant to this antibi-otic is not known; it is also unclear whether the regimenused in this study is effective in patients with sitafloxacin-resistant H. pylori strains. Obviously, the efficacy of thissitafloxacin-based regimen must be confirmed in futurestudies.

Finally, Tay et al.146 prescribed a quadruple regimencontaining PPI, bismuth, ciprofloxacin and rifabutin to agroup of 69 patients allergic to penicillin in whom at leastone standard triple treatment (usually PPI, clarithromycinand metronidazole) had failed, achieving an eradicationrate of 94%. It should be noted, however, that the authorssystematically carried out cultures and only used thisregimen in patients with strains sensitive to quinolones,which could explain the excellent results obtained in thisstudy.

In summary, in patients allergic to penicillin, bismuth-containing quadruple therapy (PPI, amoxicillin, tetracyclineand metronidazole) is suggested after failure of tripletreatment (PPI, clarithromycin and metronidazole), whiletriple therapy with PPI, levofloxacin and clarithromycinis suggested after failure of a first bismuth-containingquadruple treatment.

• Recommendation 11. Following failure of a firsttreatment with clarithromycin and a second line with lev-ofloxacin, a bismuth-containing quadruple treatment (PPI,bismuth, tetracycline and metronidazole) is recommended.

Agreement: 100%; votes: completely agree (100%). GR:strong. CE: very low.

Following the failure of a clarithromycin-containing tripleor quadruple combination, triple therapy with PPI, amoxi-cillin and levofloxacin is often recommended.5 This secondtreatment also fails sometimes, and in these cases, abismuth-containing quadruple therapy (PPI, bismuth, tetra-cycline and metronidazole) is usually prescribed.13 Thechoice of rescue treatment depends on the drugs that havebeen used in previous eradication attempts. Since repeti-tion of the same antibiotic is not recommended (with thewell-known exceptions of bismuth, amoxicillin and, to a

lesser degree, metronidazole), bismuth-containing quadru-ple therapy currently seems to be the best option, since itbasically avoids re-administration of clarithromycin and lev-ofloxacin and, therefore, is usually used in clinical practicein our setting.13

Nevertheless, experience with this quadruple regimenfollowing failure of 2 eradication treatments is very scant. ASpanish multicentre study was recently conducted to eval-uate the efficacy of bismuth-containing quadruple therapyas third-line treatment.147 One advantage of this regimenis that it is not affected by resistance to either clar-ithromycin or the fluoroquinolones (antibiotics used in thefirst and second eradication attempt, respectively). Thus,the study included consecutive patients in whom a firsttreatment with PPI, clarithromycin and amoxicillin, anda second treatment with PPI, amoxicillin and levofloxacinhad failed. A third eradication treatment was administeredwith PPI (at standard dose every 12 h), bismuth subci-trate (120 mg/6 h or 240 mg/12 h), tetracycline (between250 mg/8 h and 500 mg/6 h) and metronidazole (between250 mg/8 h and 500 mg/6 h) for 7---14 days. Two hundredpatients were included, 2 of whom were lost to follow-up.The intention-to-treat eradication rate was 65%. Adverseeffects were described in 22% of cases, none of themserious.

Following failure of 2 eradication treatments, one optionis to perform culture and antibiotic sensitivity testing inorder to select the most appropriate antibiotic combinationbased on the bacterial susceptibility.

Although this ‘‘susceptibility-guided’’ treatment optionis usually recommended in other consensuses, its superi-ority over empirical treatment has not been sufficientlyconfirmed. A sub-analysis of studies that included second-line treatments in a recent meta-analysis11 and literaturereview12 comparing the efficacy of empirical treatmentagainst therapy based on antibiotic susceptibility wasunable to demonstrate statistically significant differencesbetween both strategies. No randomised clinical trialswere identified that compared empirical treatment againstsusceptibility-guided treatment using antibiotic sensitivitytesting as third-line therapy, but the mean eradication ratein the studies that used the culture-based strategy wasonly 72%.11

As previously stated, the comments included in thisconsensus document were based on the assumption that theantibiotic susceptibility is unknown. Furthermore, most ofthe authors of this document believe there to be argumentsfor not systematically performing culture before indicatinga third eradication treatment, and that administration ofan empirical treatment should be recommended after fail-ure of a second attempt. This recommendation is basedon the fact that H. pylori culture is available in very fewcentres, it requires an invasive test (upper gastrointesti-nal endoscopy), has a sensitivity of less than 90%, and anapparent conflict between in vitro results and the in vivoeradication rate.148 Furthermore, culture only provides use-ful information on some antibiotics already used in previousfirst- (clarithromycin and metronidazole) and second-lineeradication treatments (levofloxacin), which, by definition,should not be used again.

In summary, it can be concluded that bismuth-containingquadruple empirical rescue treatment is a valid alternative


after failure of one treatment with clarithromycin andanother with levofloxacin.

• Recommendation 12. Following failure of a firsttreatment with clarithromycin and a second-line bismuth-containing quadruple treatment (PPI, bismuth, tetracyclineand metronidazole), a levofloxacin-containing treatment isrecommended.


After failure of a clarithromycin-containing triple orquadruple treatment, quadruple therapy with PPI, bismuth,tetracycline and metronidazole is often recommended.5,13

When this second treatment also fails, and in order to avoidreusing either clarithromycin or metronidazole, it has beensuggested that a triple regimen with PPI, amoxicillin andlevofloxacin be prescribed.5,13

Nevertheless, experience with this combination fol-lowing failure of 2 eradication treatments is scant. Afew years ago, a Spanish multicentre study was pub-lished that evaluated the efficacy of levofloxacin-containingtriple therapy as third-line treatment, achieving eradica-tion in approximately 70% of cases.139 These results wererecently confirmed in a larger national multicentre studythat included a total of 200 patients.142 It included con-secutive patients in whom a first treatment with PPI,amoxicillin and clarithromycin, and a second treatmentwith a bismuth-containing quadruple regimen (PPI, bismuth,tetracycline and metronidazole) had failed. A third eradica-tion treatment with PPI, amoxicillin and levofloxacin wasadministered for 10 days. The intention-to-treat eradica-tion rate was 68%. Adverse effects were described in 19% ofcases, none of them serious.

Other authors have also obtained acceptable results withthis third-line levofloxacin-containing triple treatment, witheradication rates that have varied between 60% and 86%, assummarised in Table 5.138---142

Therefore, it can be concluded that empirical triplerescue treatment with PPI, amoxicillin and levofloxacin is athird-line alternative after the failure of 2 previous eradica-tion therapies containing key antibiotics such as amoxicillin,clarithromycin, metronidazole and tetracycline. There arestill no published studies with levofloxacin-containingquadruple therapy (adding bismuth to treatment with PPI,amoxicillin and levofloxacin) which, as we have previouslyseen, increases the efficacy of second-line levofloxacin-containing triple therapy by 15%118; however, by analogy itseems reasonable that it is also a good alternative in thiscase.

• Recommendation 13. Following failure of a firstbismuth-containing quadruple treatment (PPI, bismuth,tetracycline and metronidazole), and a second-linelevofloxacin-containing regimen, quadruple concomitanttreatment (PPI, amoxicillin, clarithromycin and metronida-zole) is suggested.

Agreement: 100%; votes: completely agree (100%). GR:weak. CE: very low.

In this case (failure of a first bismuth-containing quadru-ple treatment and a second-line levofloxacin-containingtreatment), since clarithromycin was not previously used,it is suggested to use a non-bismuth quadruple treatment(concomitant), which is precisely the first-line treatmentof choice in our setting. It should be mentioned thatthis recommendation is not based on any direct evidence,but is established instead on indirect data, theoreticalassumptions and the absence of other effective therapeuticalternatives.

Another option is to re-use the bismuth with amoxicillinand tetracycline (drugs with an acquired resistance rate of<3%), but combined with other antibiotics not previouslyemployed, such as furazolidone (although this drug is notcurrently available in our setting).149 The efficacy of thisstrategy has been recently demonstrated,91 and it has beenincluded in the latest consensus therapeutic recommen-dations in China,62 where the rates of primary resistanceto clarithromycin and levofloxacin are so high that theypreclude the use of treatments with these antibiotics forH. pylori infection.

• Recommendation 14. Following the failure of a thirdtreatment, it is suggested that the need to eradicate theinfection should be re-evaluated and, if applicable, a fourthline with rifabutin (PPI, amoxicillin and rifabutin) should beprescribed.

Agreement: 100%; votes: completely agree (92.3%);mostly agree (7.7%). GR: weak. CE: very low.

H. pylori infection occasionally persists despite havingadministered 3 eradication treatments.148 Since it is notknown whether the benefit obtained by the potential erad-ication of H. pylori exceeds the risks associated with morecomplex treatment lines, the indication for eradicationtreatment and the possibility of administering maintenanceantisecretory therapy should be re-evaluated individually inthese patients. Obviously, the decision to prescribe a fourthtreatment line will be clearer the greater the benefit of H.pylori eradication, as is the case in patients with peptic ulcer(especially if they have had previous complications) or withgastric MALT lymphoma.

A recent literature review evaluated the role ofrifabutin---an antibiotic with high in vitro activity againstH. pylori---in the treatment of this infection.150 The meanrate of H. pylori resistance to rifabutin (calculated from11 studies, including 2982 patients) was 1.3%. When onlystudies that included patients with no previous eradica-tion treatments were considered, this figure was even lower(0.6%). Overall, the mean H. pylori eradication rate (byintention-to-treat analysis) with combinations that includedrifabutin (1008 patients) was 73%. Specifically, the erad-ication rate for the fourth/fifth-line rifabutin-containingtreatments (95 patients) was 79%.139,151---156 Most studies used300 mg/day of rifabutin for the treatment of H. pylori infec-tion, a dose that seems to be more effective than the150 mg/day dose. The optimal duration of treatment hasnot been established, but 10---12 days is generally recom-mended. The mean incidence of adverse effects was 22%; ofthese, myelotoxicity, although rare, was the most important(so follow-up complete blood count should be performed


at the end of treatment); to date, leukopenia has resolvedwithout incident in all patients within a few days of com-pleting treatment, and no infections or other complicationsassociated with the myelotoxicity have been described.150

These findings have recently been confirmed in a Span-ish multicentre study that evaluated the efficacy of a fourthempirical rifabutin-containing rescue treatment in patientsin whom 3 previous eradication attempts had failed (thefirst with PPI, clarithromycin and amoxicillin; the secondwith a quadruple therapy with PPI, bismuth, tetracyclineand metronidazole, and a third with PPI, amoxicillin andlevofloxacin).157 A fourth eradication treatment with PPI,amoxicillin (1 g/12 h) and rifabutin (150 mg/12 h) was admin-istered for 10 days. One hundred consecutive patientswere included. Eight patients did not take the medicationcorrectly (in 6 cases due to adverse effects). The intention-to-treat eradication rate was 50%. Adverse effects werereported in 30 patients (30%). Mild myelotoxicity, observedin 4% of patients, resolved spontaneously in all cases aftercompletion of treatment. It was therefore concluded thateven after failure of 3 previous treatments, a fourth empir-ical rescue therapy with rifabutin (together with PPI andamoxicillin) may be effective for eradicating H. pylori infec-tion in approximately half of cases. Finally, although theevidence in this respect is very limited,146,158 when multipleeradication attempts have failed, combining bismuth withrifabutin in order to increase eradication efficacy can beconsidered.

In summary, after the failure of a third treatment,the need to eradicate the infection and the possibility ofadministering maintenance antisecretory therapy should becarefully evaluated. If eradication is considered necessary,the need for a fourth line of treatment, for example withrifabutin, should be assessed individually, with strict patientmonitoring and follow-up.

• Recommendation 15. In patients with uncompli-cated duodenal ulcer who do not require non-steroidalanti-inflammatory drugs (NSAID)/aspirin, antisecretorytreatment should not be maintained after completing H.pylori eradication treatment.

Agreement: 100%; votes: completely agree (92.9%);mostly agree (7.1%). GR: strong. CE: high.

Initially, most authors who used PPIs in eradication ther-apies for uncomplicated duodenal ulcer disease (with nogastrointestinal bleeding or perforation) prolonged the useof these drugs for 2---4 weeks after conclusion of antibiotictreatment in order to ensure ulcer healing.159 However, ithas been found that limiting administration of PPIs to theduration of antibiotic treatment is sufficient to achieve ahigh rate of ulcer healing in these patients. A systematicreview of the medical literature identified 24 studies with atotal of 2378 patients in which ulcer healing was evaluatedafter 7 days of PPI plus 2 antibiotics.160 The overall (both suc-cess and failure of H. pylori eradication) mean healing rate(intention-to-treat) was 86%. This figure rose to 95% whenonly those patients in whom the infection had been eradi-cated were included. The meta-analysis of the 6 randomisedstudies161---166 that compared efficacy in terms of ulcer heal-ing with PPI plus 2 antibiotics for 7 days versus the same

treatment with PPI prolonged for a further 2---4 weeks160

found ulcer healing in 91% and 92% of cases, respectively.The OR for this comparison was 1.11 (95% CI = 0.71---1.74),with homogeneous results. Finally, a sub-analysis of patientswith duodenal ulcer found similar results (OR 1.14, with95% CI = 0.71---184). Two other randomised studies were con-ducted subsequent to the publication of this meta-analysis,with similar outcomes.167,168

In summary, it can be concluded that a PPI administeredfor the same duration as antibiotic therapy is sufficientto obtain a high rate of healing in uncomplicated duode-nal ulcer in patients who do not take NSAID or aspirin.Nevertheless, in the case of complicated duodenal ulcers(gastrointestinal bleeding, perforation), it is prudent toadminister antisecretory agents until H. pylori eradicationis confirmed.

• Recommendation 16. In patients with gastric ulcerwho do not require NSAID/aspirin, antisecretory treatmentshould be maintained for 4---8 weeks after completingH. pylori eradication treatment.

Agreement: 100%; votes: completely agree (100%). GR:strong. CE: moderate.

Two medical literature reviews published more than adecade ago provide arguments in favour of not prolong-ing antisecretory treatment in patients with gastric ulcer,in line with the approach taken with duodenal ulcers. Thefirst of these concludes that ‘‘H. pylori eradication wasfound to induce a better response in peptic ulcer healing,regardless of diagnosis (duodenal or gastric)’’.169 The othersystematic review reached the conclusion that ‘‘the erad-ication of H. pylori cures both gastric and duodenal ulcer,and the cure rates are similar’’.170 From these data, it canbe concluded that the healing rate with H. pylori eradica-tion treatment was similar for both gastric and duodenalulcers.

However, recent studies suggest the need to prolong anti-secretory treatment, especially in gastric ulcers larger than1 cm. An initial study documented 100% healing of gastriculcers smaller than 1 cm 8 weeks after the administrationof a 2-week eradication treatment.171 The healing rate wasconsiderably reduced when the ulcers were larger than 1 cm;it is important to note that all the ulcers that had nothealed at 8 weeks disappeared after additional PPI treat-ment. One of the randomised studies that provides highlyrelevant information on this subject evaluated gastric ulcerhealing in patients infected with H. pylori after 1-week erad-ication treatment or 8-week PPI therapy.172 It was foundthat the healing rate 8 weeks after eradication treatmentwas exponentially reduced according to the size of the ulcer(89% for ulcers <1 cm, 54% for ulcers between 1 and 1.4 cmand 5% for those ≥1.5 cm), while it was significantly higherin the group treated with PPI for 8 weeks (100% for ulcers<1 cm, 77% for ulcers between 1 and 1.4 cm and 77% for those≥1.5 cm).172

More recently, another randomised study was publishedcomparing the administration of eradication therapy aloneversus this therapy followed by a PPI for 3 weeks.173 Gas-tric ulcer healing at 4 weeks was lower in patients treatedwith triple therapy alone, without subsequent PPIs (64% vs


82%). Similarly, in patients with unhealed gastric ulcer, 1additional 4-week cycle of a PPI (esomeprazole) increasedthis percentage to 89---96%. It should be noted that this studyhas some methodological defects, such as the exclusion ofpatients with ulcers >2 cm and excessively early endoscopicfollow-up of the healing (4 weeks) for a gastric ulcer.

Finally, a recent Japanese study randomised 115 patientswith gastric ulcer stratified according to the size of thelesion (<0.5 cm, 0.5---1.5 cm and >1.5 cm) to receive erad-ication treatment (for 1 week) plus 7 weeks with PPI versuseradication treatment plus 7 weeks of a cytoprotectiveagent.168 The ulcer healing rates at 8 weeks were significan-tly higher in the group with eradication treatment plus PPI.Consistent with previous studies, the ulcer healing resultswith eradication treatment plus PPI were better for gastriculcers >1.5 cm (85% vs 43%).

In summary, the scant evidence available points toa higher ulcer healing rate with eradication treatmentfollowed by PPI for gastric ulcers associated with H. pyloriinfection. All the aforementioned studies168,172,173 found alack of healing of up to 20% with eradication treatmentalone, or even higher in the case of large ulcers. It istherefore recommended that after completing eradicationtreatment, antisecretory therapy should be prolongedbetween 4 and 8 weeks in gastric ulcers, especially in thoselarger than 1 cm. Finally, it should be remembered thatafter completing eradication treatment and subsequent PPI,endoscopic surveillance should be carried out to confirmulcer healing.

• Recommendation 17. In patients with gastrointestinalbleeding due to peptic ulcer, eradication of H. pylorieliminates virtually all recurrences; therefore, once theeradication has been confirmed, and in the absence ofNSAID/aspirin treatment, antisecretory maintenance treat-ment should not be administered.

Agreement: 100%; votes: completely agree (100%). GR:strong. CE: high.

Peptic ulcer is the leading cause of upper gastrointesti-nal bleeding, and H. pylori is the main aetiological factorin gastroduodenal ulcer disease.174 Long-term antisecretorymaintenance therapy has been the standard treatment toprevent re-bleeding in patients with a previous episode ofgastrointestinal bleeding from peptic ulcer. Although it isamply known that H. pylori eradication is associated with adrastic decrease in ulcer recurrence, the efficacy of eradica-tion treatment in the prevention of re-bleeding from pepticulcer was unknown until recently.

A meta-analysis that followed the Cochrane Collabo-ration methodology was published in 2004 comparing theefficacy of H. pylori eradication treatment with antise-cretory treatment for the prevention of re-bleeding frompeptic ulcer.175,176 An initial sub-analysis included 7 stud-ies with a total of 578 patients: the average percentage ofre-bleeding in the eradication treatment group was 2.9%vs 20% (OR = 0.17; 95% CI = 0.10---0.32) in the group withneither eradication treatment nor maintenance antisecre-tory treatment. The second sub-analysis included 3 studieswith a total of 470 patients: the average percentage ofre-bleeding in the eradication treatment group was 1.6%

vs 5.6% (OR = 0.24; 95% CI = 0.09---0.67) in the group givenmaintenance antisecretory treatment but no eradicationtreatment. Several studies have evaluated the incidence ofre-bleeding in patients with confirmed H. pylori eradicationwho were followed-up without administering maintenanceantisecretory treatment.177---196 Given that the duration offollow-up varies notably among the various studies, thefollow-up periods of each study were taken into account andthe respective annual re-bleeding rate was calculated (perpatient and year of follow-up). Thus, the overall follow-upwas 1913 patient-years, and 13 re-bleeding episodes weredetected among patients in whom the bacterium had beeneradicated; the annual recurrence was 0.88% per patientand year of follow-up.

These favourable results have been confirmed in a recentSpanish multicentre study that prospectively included 1000patients with gastrointestinal bleeding from a peptic ulcer inwhom H. pylori infection had been eradicated and antisecre-tory treatment was not subsequently prescribed.197 Threere-bleeding episodes were detected at 1 year of follow-up(in 2 cases after NSAID use and in 1 after H. pylori reinfec-tion) and another 2 episodes at 2 years (1 after NSAID use andanother after H. pylori reinfection). The cumulative inci-dence of re-bleeding was 0.5%, and the incidence rate was0.15% per patient-year. From the aforementioned results,it can be deduced that treatment of H. pylori infection ismore effective than antisecretory treatment (either withor without maintenance antisecretory agents) in prevent-ing peptic ulcer re-bleeding. Consequently, the presence ofH. pylori infection should be evaluated in all patients withgastrointestinal bleeding due to peptic ulcer, and eradica-tion treatment prescribed in those who are infected. Oncethe eradication has been confirmed, it is not necessaryto administer antisecretory maintenance treatment (if thepatient does not require NSAID), as H. pylori eradicationeliminates almost all bleeding recurrences. Nevertheless,it seems prudent that in a peptic ulcer that has presentedcomplications (e.g. gastrointestinal bleeding), antisecretorydrugs should be administered until H. pylori eradication isconfirmed.

Conflict of interests of the participants at theIV Spanish Consensus Conference on thetreatment of Helicobacter pylori infection

Javier P. Gisbert: scientific consultancy, support for researchand training activities: Almirall, Allergan, AstraZeneca,Casen Recordati, Nycomed.

Javier Molina-Infante: scientific consultancy: CasenRecordati; training activities: Allergan, Zambón.

Javier Amador: none.Fernando Bermejo: none.Luis Bujanda: none.Xavier Calvet: training activities: Allergan.Manuel Castro-Fernández: training activities: Allergan.Antonio Cuadrado: none.J. Ignasi Elizalde: none.Emili Gene: none.Fernando Gomollón: none.Ángel Lanas: none.


Carlos Martín de Argila: training activities: Allergan,Casen Recordati.

Fermín Mearin: none.Miguel Montoro: scientific consultancy: Almirall.Ángeles Pérez-Aisa: training activities: Allergan.Emilio Pérez-Trallero: none.Adrián G. McNicholl: training activities: Allergan.

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